SCN genes, their function and associated disorders



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Sodium channels and related disorders
Information about SCN1A

History of SCN1A Research

  • 1952
  • Hodgkin et al.

    Discovery of the action potential.

  • 1978
  • Dravet

    First description of Dravet Syndrome

  • 1997
  • Scheffer et al.

    Defining genetic epilepsy with febrile seizures plus (GEFS+)

  • 1998
  • Guerrini et al.

    Seizure worsening due to sodium channel blockers in Dravet syndrome

  • 2000
  • Escayg et al.

    First association of SCN1A with GEFS+

  • 2000
  • Chiron et al.

    Stiripentol treatment for Dravet syndrome

  • 2001
  • Claes et al.

    De novo mutations in SCN1A cause Dravet syndrome

  • 2006
  • Yu et al.

    Selective loss of GABAergic interneurons results in hyperexcitability of pyramidal neurons, leading to seizures in SCN1A mice

  • 2006
  • Berkovic et al.

    The misconception of vaccine encephalopathy associated with Dravet syndrome

  • 2007/2009/2012/2017
  • Harkin et al.
    Depienne et al.
    Brunklaus et al.
    Ishii et al.

    Genotype phenotype associations in large SCN1A cohorts

  • 2011
  • Payandeh et al.

    First image of the crystal structure of a voltage-gated sodium channel

  • 2012
  • Han et al.

    Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission

  • 2013
  • Liu et al.

    Dravet iPSC-derived neuron work

  • 2017
  • Devinsky et al.

    Cannabidiol treatment for Dravet syndrome

  • 2019
  • Lagae et al.

    Fenfluramine treatment for Dravet syndrome

  • 2020
  • Han et al.

    Antisense oligonucleotide treatment in Dravet mouse model

SCN1A -related disorders

SCN1A , encoding the alpha 1 subunit of the voltage-gated sodium channel Nav1.1, is associated with a wide clinical spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). Dravet syndrome (DS) is the prototypic DEE presenting with recurrent, often prolonged febrile and afebrile seizures, including hemiclonic, generalized tonic-clonic seizures and status epilepticus. Subsequently other seizure types, such as myoclonic and atypical absence seizures, emerge as well as long-term problems with learning, motor development and behaviour. In contrast, individuals with GEFS+ phenotypes have well controlled epilepsy with normal cognition. Apart from epilepsy, SCN1A has also been associated with familial hemiplegic migraine, a subtype of migraine with aura characterised by hemiparesis during the attacks.

Treatment options

For more information on possible treatment options, please visit the appropriate family organization website: Family organisations

Summary of clincal information curated in the SCN Portal


Number of patients with data in this category = 355


FS +: Focal seizure; GEFS +: Generalized epilepsy with febrile seizures plus; MAE: Myoclonic atonic epilepsy


Number of patients with data in this category = 338


FS +: Focal seizure; GEFS +: Generalized epilepsy with febrile seizures plus; MAE: Myoclonic atonic epilepsy


Number of patients with data in this category = 244



Number of patients with data in this category = 338

Number of patients with data in this category = 272


Status Epilepticus

MRI abnormality


Number of patients with data in this category = 309

Number of patients with data in this category = 314



Autism

Aquired movement disorder


Number of patients with data in this category = 270

Number of patients with data in this category = 263


Seizures improved

Seizures worsend

Information about SCN2A

History of SCN2A Research

SCN2A -related disorders

SCN2A -related disorders are characterized by a wide clinical spectrum ranging from benign familial infantile seizures to developemental and epileptic encephalopathy. Furthermore, SCN2A is one of the most prominent monogenic causes of autism spectrum disorders. Variants causing both gain and loss of function have been identified as the underlying pathomechanism. Correlations between functional outcome and clinical phenotype includes: autism and/or late onset epilepsy for individuals with loss of function variants and neonatal onset self-limiting epilepsy or neonatal/infantile DEE with gain of function variant. As subset of individuals with self-limiting epilepsy develop episodic ataxia later in childhood.

Treatment options

For more information on possible treatment options, please visit the appropriate family organization website: Family organisations

Summary of clincal information curated in the SCN Portal


Number of patients with data in this category = 413


DEE: Developmental and Epileptic Encephalopathies; ASD: Autism spectrum disorder


Number of patients with data in this category = 140


DEE: Developmental and Epileptic Encephalopathies; ASD: Autism spectrum disorder


Number of patients with data in this category = 176



Number of patients with data in this category = 358

Number of patients with data in this category = 266


Seizures

EEG abnormality


Number of patients with data in this category = 200


Seizures

Information about SCN3A

History of SCN3A Research

SCN3A -related disorders

SCN3A -related disorders are characterized mainly by epilepsy often associated with brain malformations such as polymicrogyria (abnormal gyration of the brain). Affected individuals often have intellectual disability. Seizure types varies, and includes focal, febrile, myoclonic and tonic seizures among others. Functional studies have revealed both gain and loss of function as underlying pathomechanism. Because of a small number of known affected individuals, correlations between functional outcome, genotype and phenotype are still sparse. The limited data there is, suggests that brain malformations are mainly seen in individuals with gain of function variants, while epilepsy and intellectual disability are seen in both individuals with gain and loss of function variants.

Treatment options

For more information on possible treatment options, please visit the appropriate family organization website: Family organisations

Summary of clincal information curated in the SCN Portal


Number of patients with data in this category = 44


GEFS +: Generalized epilepsy with febrile seizures plus; DEE: Developmental and Epileptic Encephalopathies; PMG: Polymicrogyria; ASD: Autism spectrum disorder


Number of patients with data in this category = 12


Information about SCN8A

History of SCN8A Research

SCN8A -related disorders

SCN8A, encoding the alpha subunit of the voltage-gated sodium channel Nav1.6, is associated with a wide clinical spectrum of epilepsies ranging from benign familial infantile seizures (BFIS), over an intermediate phenotype with treatable seizures and mild-moderate intellectual disability, to severe developmental and epileptic encephalopathies (DEEs). SCN8A-DEE is characterized by early onset intractable seizures, cognitive impairment, movement disorders, cortical visual impairment and severe gastrointestinal symptoms. The seizures are often prolonged focal hypomotor and occur in clusters, with prominent vegetative symptoms, evolving to clonic or bilateral tonic-clonic manifestations. Spasm-like episodes, cortical myoclonus, and recurrent episodes of status epilepticus are also common. In contrast, individuals with BFIS have well controlled self-limiting epilepsy with no other neurological deficits and normal cognition. In addition, rare clinical presentations with ID, autism spectrum disorder and movement disorders without epilepsy have been described.

Treatment options

For more information on possible treatment options, please visit the appropriate family organization website: Family organisations

Summary of clincal information curated in the SCN Portal


Number of patients with data in this category = 392


DEE: Developmental and Epileptic Encephalopathies; BFIE: Benign Familial Infantile Epilepsy; GGE: Genetic Generalized Epilepsy; IE: Intermediate Epilepsy; UE: Unclassifiable Epilepsy; NDDwoe: Neurodevelopmental Disorder without Epilepsy


Number of patients with data in this category = 302


DEE: Developmental and Epileptic Encephalopathies; BFIE: Benign Familial Infantile Epilepsy; GGE: Genetic Generalized Epilepsy; IE: Intermediate Epilepsy; UE: Unclassifiable Epilepsy; NDDwoe: Neurodevelopmental Disorder without Epilepsy


Number of patients with data in this category = 287


For Families



What are SCN-related disorders?


Gene specific videos


SCN1A family video



SCN2A family video





SCN-Genes and related disorders

If your family has received a diagnosis of an SCN-related neurodevelopmental disorder, you've probably never heard of it before. That's okay. Your doctors probably haven't either! But the Educational Science community is here to help.

In this section, you can find a series of short explainer videos that are designed to help patients, families, and clinicians to learn about SCN-related neurodevelopmental disorders in plain language. Over time, we'll be adding more content to cover all SCN genes and related topics.

The series starts with an overview video about all SCN-genes included in this Portal:SCN1A, SCN2A, SCN3A, SCN8A.

Next, we present a comprehensive video on SCN1A-related disorders and introductory video on SCN2A-related disorders.

From this videos you'll learn:

  • Scientific terms (such as genes, proteins and variants/mutations) that will help you understand SCN-related disorders
  • What causes SCN-related disorders
  • How SCN-related disorders are diagnosed
  • The symptoms of SCN-related disorders
  • Existing options for symptom treatment, as there is currently no cure for SCN-related disorders
  • Where to find support

Analyse your variants

Enter variant

Variant Information

Clinical significance according to ClinVar

Variant Information


Individuals with the same variant in the SCN Portal


FS +: Focal seizure; GEFS +: Generalized epilepsy with febrile seizures plus; MAE: Myoclonic atonic epilepsy; DEE: Developmental and Epileptic Encephalopathies; BNFS: Benign Familial Neonatal Seizures; EOEE: Early-Onset Epileptic Encephalopathies; ASD: Autism Spectrum Disorder; PMG: Polymicrogyria


FS +: Focal seizure; GEFS +: Generalized epilepsy with febrile seizures plus; MAE: Myoclonic atonic epilepsy; DEE: Developmental and Epileptic Encephalopathies; BNFS: Benign Familial Neonatal Seizures; EOEE: Early-Onset Epileptic Encephalopathies; ASD: Autism Spectrum Disorder; PMG: Polymicrogyria

Custom variant analysis


Compare your variant with other variants in the SCN Portal



Show paralogs


FS +: Focal seizure; GEFS +: Generalized epilepsy with febrile seizures plus; MAE: Myoclonic atonic epilepsy; DEE: Developmental and Epileptic Encephalopathies; BNFS: Benign Familial Neonatal Seizures; EOEE: Early-Onset Epileptic Encephalopathies; ASD: Autism Spectrum Disorder; PMG: Polymicrogyria


Paralog conservation score
Missense constraint score
Pathogenic variant enrichment

Analyse your variants

Filter variants form the SCN Portal

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PER: Pathogenic enriched region on linear protein sequence; PER3D: Pathogenic enriched region on protein structure

Custom variant exploration



Selected variants are displayed in 2D (lolliplot) and 3D (protein structure).

Reference population missense variants (gnomAD)
Pathogenic enriched regions (PER)

PTV: Protein truncating variant; PER: Pathogenic enriched region


The following transcripts were used: SCN1A: ENST00000303395; SCN2A: ENST00000283256; SCN3A: ENST00000283254; SCN8A: ENST00000354534


UniProt: P35498
PDB: 7DTD
UniProt: Q99250
PDB: 6J8E
UniProt: Q99250
Aligend to PDB: 6J8E
UniProt: Q9UQD0
Aligend to PDB: 6J8E

All variants aligned to SCN2A and vizualized on Nav1.2

All Proteins
Aligend to PDB: 6J8E

Pathogenic variant burden across SCN-genes

UniProt: Q99250
Aligend to PDB: 6J8E

FS +: Focal seizure; GEFS +: Generalized epilepsy with febrile seizures plus; MAE: Myoclonic atonic epilepsy; DEE: Developmental and Epileptic Encephalopathies; BNFS: Benign Familial Neonatal Seizures; EOEE: Early-Onset Epileptic Encephalopathies; ASD: Autism Spectrum Disorder; PMG: Polymicrogyria


All functional measures are displayed on the Nav1.2 structure: 6J8E

Compare variants of the SCN Portal

Group 1: select color


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Group 2: select color


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Comparison interface


The following transcripts were used: SCN1A: ENST00000303395; SCN2A: ENST00000283256; SCN3A: ENST00000283254; SCN8A: ENST00000354534

All variants aligned to SCN2A and vizualized on Nav1.2

Aligend to PDB: 6J8E


FS +: Focal seizure; GEFS +: Generalized epilepsy with febrile seizures plus; MAE: Myoclonic atonic epilepsy; DEE: Developmental and Epileptic Encephalopathies; BNFS: Benign Familial Neonatal Seizures; EOEE: Early-Onset Epileptic Encephalopathies; ASD: Autism Spectrum Disorder; PMG: Polymicrogyria

About

Portal version

This is the alpha version of the SCN Portal.

The SCN Portal is a coalition of investigators seeking to aggregate and harmonize data generated to study SCN-related disorders, and to make summary data interactively accessible for the wider scientific community, while providing educational resources for everyone. The goals of this project are:


  • Providing information on SCN-related disorders

  • Supporting research on SCN-related disorders

  • Linking researchers, clinicians and families

  • Providing support in variant interpretation and classification


Teams and People

The current version of the SCN Portal has been developed by an international team of researchers and clinicians:

Team Leaders

Andreas Brunklaus (Glasgow, UK): SCN1A Clinical & genetic data

Stephanie Schorge (London, UK): Functional data curation

Rikke Møller (Dianalund, DK): SCN1A , SCN2A , SCN8A Clinical & genetic data

Ingo Helbig (Philadelphia, US): SCN2A Clinical & genetic data

Jen Q Pen (Cambride, US): SCN1A High-throughput functional data

Alfred George (Chicago, US): SCN1A & SCN2A High-throughput functional data

Dennis Lal (Cleveland, US): General concept, web development, bioinformatics, video production

Clinical & Genetic Data

Katrine Johannesen

Ingo Helbig

Sameer Zuberi

Molecular Data

Holger Lerche

Massimo Mantegazza

Sandrine Cestele

Web Development

Tobias Brünger

Chiara Klöckner

Eduardo Perez-Palma

Marie Macnee

Bioinformatics

Tobias Brünger

Eduardo Perez-Palma

Chiara Klöckner

Marie Macnee

Patrick May

Johannes Lemke

Video

Arthur Stefanski

Alina Ivaniuk

Andreas Brunklaus

Katrine Johannesen

Family outreach

Mary Anne Meskis : SCN1A

Veronica Hood : SCN1A

Leah Schust : SCN2A

Impressum

We object to any commercial use and disclosure of data.

Copyright and use: The authors grants you the right of use to make a private copy for personal purposes. However, you are not entitled to change and/or pass on the materials or publish them yourself. Upon request, you will receive free information about the personal data stored about you. To do so, please contact the administrator.

No liability: The contents of this web project have been carefully checked and created to the best of our knowledge. But for the information presented here is no claim to completeness, timeliness, quality and accuracy. No responsibility can be accepted for any damage caused by reliance on or use of the contents of this website.

Terms of Use

All data here are publicly for the benefit of the wider biomedical community. You can freely explore the data, and we encourage the use and publication of results generated from these data. However, we encourage you to contact us before embarking on analyses to check if your proposed analysis overlaps with work currently underway by our team. Further, we request that you actively acknowledge and give attribution to the SCN Portal project, and link back to the relevant page, wherever possible. All users of our data agree to not attempt to reidentify participants. Our data set has been subjected to extensive quality control, but may be imperfect so errors may remain. If you spot any results that seem impossible, or have suggestions for SCN Portal improvements:

Contact us that we can improve.

Data Generation

Data has been curated in a community effort.